increased expressivity of gene ontology annotations - biocuration 2013

Increased Expressivity of Gene Ontology Annotations

Huntley RP, Harris MA, Alam-Faruque Y, Carbon SJ, Dietze H, Dimmer E, Foulger R, Hill DP, Khodiyar V, Lock

A, Lomax J, Lovering RC, Mungall CJ, Mutowo-Muellenet P, Sawford T, Van Auken K, Wood V

The Gene Ontology

• A vocabulary of 37,500* distinct, connected descriptions that can be applied to gene products

• That’s a lot…– How big is the space of possible descriptions?

*April 2013

Current descriptions miss details

• Author:– LMTK1 (Aatk) can negatively control axonal outgrowth

in cortical neurons by regulating Rab11A activity in a Cdk5-dependent manner

– http://www.ncbi.nlm.nih.gov/pubmed/22573681

• GO:– Aatk: GO:0030517 negative regulation of axon

extension

• GO terms will always be a subset of total set of possible descriptions– We shouldn’t attempt to make a term for everything

• T63 Toxic effect of contact with venomous animals and plants

Term from ICD-10, a hierarchical medical billing code system use to ‘annotate’ patient records

• T63 Toxic effect of contact with venomous animals and plants– T63.611 Toxic effect of contact with Portugese

Man-o-war, accidental (unintentional)

• T63 Toxic effect of contact with venomous animals and plants– T63.611 Toxic effect of contact with Portugese

Man-o-war, accidental (unintentional) – T63.612 Toxic effect of contact with Portugese

Man-o-war, intentional self-harm

• T63 Toxic effect of contact with venomous animals and plants– T63.611 Toxic effect of contact with Portugese

Man-o-war, accidental (unintentional) – T63.612 Toxic effect of contact with Portugese

Man-o-war, intentional self-harm – T63.613 Toxic effect of contact with Portugese

Man-o-war, assault

• T63 Toxic effect of contact with venomous animals and plants– T63.611 Toxic effect of contact with Portugese

Man-o-war, accidental (unintentional) – T63.612 Toxic effect of contact with Portugese

Man-o-war, intentional self-harm – T63.613 Toxic effect of contact with Portugese

Man-o-war, assault • T63.613A Toxic effect of contact with Portugese Man-

o-war, assault, initial encounter • T63.613D Toxic effect of contact with Portugese Man-

o-war, assault, subsequent encounter • T63.613S Toxic effect of contact with Portugese Man-

o-war, assault, sequela

Post-composition

• Curators need to be able to compose their complex descriptions from simpler descriptions (terms) at the time of annotation

• GO annotation extensions• Introduced with Gene Association Format (GAF) v2

– Also supported in GPAD

• Has underlying OWL description-logic model

http://www.geneontology.org/GO.format.gaf-2_0.shtml

“Classic” annotation model

• Gene Association Format (GAF) v1– Simple pairwise model– Each gene product is associated with an (ordered) set

of descriptions• Where each description == a GO term

http://www.geneontology.org/GO.format.gaf-1_0.shtml

GO annotation extensions

• Gene Association Format (GAF) v1– Simple pairwise model– Each gene product is associated with an (ordered) set of

descriptions• Where each description == a GO term

• Gene Association Format (GAF) v2 (and GPAD)– Each gene product is (still) associated with an (ordered) set of

descriptions– Each description is a GO term plus zero or more relationships to

other entities• Entities from GO, other ontologies, databases• Description is an OWL anonymous class expression (aka description)

http://www.geneontology.org/GO.format.gaf-2_0.shtml

“Classic” GO annotations are unconnected

sty1

DB Object Term Ev Ref ..PomBase sty1

SPAC24B11.06c GO:0034504 IMP PMID:9585505 .. .. ..

PomBase sty1SPAC24B11.06c

GO:0034599 IMP PMID:9585505 .. ..

PomBase pap1SPAC1783.07c

GO:0036091 IMP PMID:9585505 ..

protein localization to

nucleus[GO:0034504]

cellular response to oxidative stress

[GO:0034599]

pap1

positive regulation of transcription from pol II promoter in response to

oxidative stress[GO:0036091]

Now with annotation extensions

sty1

DB Object Term Ev Ref ExtensionPomBase sty1

SPAC24B11.06c GO:0034504protein localization to nucleus

IMP PMID:9585505 .. happens_during(GO:0034599),has_input(SPAC1783.07c)

..

PomBase pap1SPAC1783.07c

GO:0036091 IMP PMID:9585505 has_reulation_target(…)

protein localization to

nucleus[GO:0034504]

cellular response to oxidative stress

[GO:0034599]

happensduring

pap1has input

positive regulation of transcription from pol II promoter in response to

oxidative stress[GO:0036091]

has regulationtarget

<anonymousdescription>

<anonymousdescription>

PomBase web interface – sty1

http://www.pombase.org/spombe/result/SPAC24B11.06c

http://www.pombase.org/spombe/result/SPAC1783.07c

pap1

Where do I get them?

• Download– http://geneontology.org/GO.downloads.annotations.shtml

• MGI (22,000)• GOA Human (4,200)• PomBase (1,588)

• Search and Browsing– Cross-species

• AmiGO 2 – http://amigo2.berkeleybop.org - poster#57• QuickGO (later this year) - http://www.ebi.ac.uk/QuickGO/

– MOD interfaces• PomBase – http://bombase.org

Query tool support: AmiGO 2Annotation extensions make useof other ontologies• CHEBI• CL – cell types• Uberon – metazoan anatomy• MA – mouse anatomy• EMAP – mouse anatomy• ….

CL– http://amigo2.berkeleybop.org

CL, Uberon– http://amigo2.berkeleybop.org

CL, Uberon– http://amigo2.berkeleybop.org

Curation tool support

• Supported in– Protein2GO (GOA, WormBase) [poster#97]– CANTO (PomBase) [poster#110]– MGI curation tool

Analysis tool support

• Currently: Enrichment tools do not yet support annotation extensions– Annotation extensions can be folded into an

analysis ontology - http://galaxy.berkeleybop.org • Future: Analysis tools can use extended

annotations to their benefit– E.g. account for other modes of regulation in their

model– Tool developers: contact us!

Challenge: pre vs post composition

• Curator question: do I…– Request a pre-composed term via TermGenie[*]?– Post-compose using annotation extensions?

See Heiko’s TermGenie talk tomorrow & poster #33

Challenge: pre vs post composition

• Curator question: do I…– Request a pre-composed term via TermGenie?– Post-compose using annotation extensions?

http://code.google.com/p/owltools/wiki/AnnotationExtensionFolding

• From a computational perspective:– It doesn’t matter, we’re

using OWL– 40% of GO terms have OWL

equivalence axioms

protein localization

[GO:0008104]

Nucleus [GO:0005634

]

end_location

≡

⊓

protein localization to nucleus[GO:0034504]

Curation Challenges

• Manual Curation– Fewer terms, but more degrees of freedom– Curator consistency• OWL constraints can help

• Automated annotation– Phylogenetic propagation– Text processing and NLP

Similar approaches and future directions

• Post-composition has been used extensively for phenotype annotation– ZFIN [poster#95]– Phenoscape [next talk]

• Future:– A more expressive model that bridges GO with

pathway representations

Conclusions

• Description space is huge– Context is important– Not appropriate to make a term for everything– OWL allows us to mix and match pre and post

composition• Number of extension annotations is growing• Annotation extensions represent untapped

opportunity for tool developers

Acknowledgments

• GO Consortium, model organism and UniProtKB curators• GO Directors• PomBase developers:

– Mark McDowell, Kim Rutherford

• Funding– GO Consortium NIH 5P41HG002273-09– UniProtKB GOA NHGRI U41HG006104-03– British Heart Foundation grant SP/07/007/23671– Kidney Research UK RP26/2008– PomBase - Wellcome Trust WT090548MA– MGD NHGRI HG000330